Parkinson's disease is a progressive neurodegenerative disorder caused by a loss of the cell bodies of dopaminergic neurons from the substantia nigra and degeneration of nerve terminals in the striatum resulting in low levels of dopamine in the substantia nigra and corpus striatum. Parkinson's disease is characterized by chronic, progressive motor dysfunction and its main symptoms are tremor at rest, muscle rigidity and a decrease in the frequency of voluntary movements (hypokinesia) with difficulty in stopping, starting and turning when walking. A persistent tremor is superimposed on hypertonicity of opposing muscle groups and initiation of movements becomes increasingly difficult and slow. In advanced stages, patients' movements become virtually "frozen" and patients are unable to care for themselves. Studies have shown that the symptoms of Parkinson's disease appear when the striatal dopamine content is reduced to 20-40% of normal. As Parkinson's disease is associated with a loss of dopamine from the striatum, it is commonly treated with drugs which replace dopamine, the most commonly used of these being levodopa. Levodopa is converted by dopa decarboxylase into dopamine in the brain and it is this dopamine which exerts a therapeutic effect. However, although levodopa is well absorbed from the small intestine, much of it is inactivated by monoamine oxidase in the wall of the intestine. Also, the plasma half-life of levodopa is short and about 95% of the drug is converted to dopamine in peripheral tissues, where dopa decarboxylase is widespread, with the result that less than 1% enters the brain. Consequently levodopa has to be administered in large and frequent doses. In addition, the production of dopamine in peripheral tissues gives rise to unwanted side effects. Accordingly, levodopa is normally given in combination with other drugs to enhance the effects of levodopa in the brain and minimize its peripheral effects. In particular, levodopa is usually given in combination with a peripheral dopa decarboxylase inhibitor which cannot cross the blood-brain barrier, such as carbidopa, which inhibits the breakdown of levodopa to dopamine outside the brain, thereby reducing peripheral unwanted effects. The inhibitor also ensures that a relatively large amount of an oral dose of levodopa reaches the brain and thus enables the dose of levodopa to be reduced which also reduces peripheral side effects. In addition, a peripheral dopamine antagonist which does not penetrate the blood-brain barrier, such as domperidone, may also be administered to reduce the nausea and vomiting side effects of levodopa.
In addition to the side effects mentioned above, further undesirable effects are associated with the prolonged use of levodopa. In particular, many patients develop involuntary choreiform movements, which are the result of excessive activation of dopamine receptors. These movements usually affect the face and limbs and can become very severe. Such movements disappear if the dose of levodopa is reduced but this causes rigidity to return. Moreover, the margin between the beneficial and the unwanted effect appears to become progressively narrower as the period of levodopa treatment increases. The traditional method of combating this effect is to increase the frequency of administration of levodopa while keeping the overall dose steady. This approach reduces end-of-dose deterioration and diminishes the likelihood of the patient developing the dyskinesias that occurs with high peak doses.
A further complication of long-term levodopa treatment is the development of rapid fluctuations between mobility and immobility for periods ranging from a few minutes to a few hours. This phenomenon is known as the "on-off effect". The "on" state being the preferred state during which nearly normal motor functioning can be attained and the "off" state being characterized by dystonic postures during periods of decreased mobility. Indeed, this effect can produce such an abrupt loss of mobility that the patient may suddenly stop while walking or be unable to rise from a chair in which he had sat down normally a few moments earlier. This effect is commonly unaffected by manipulation of the dose of levodopa and may require treatment with alternative drugs.
In addition to the above long-term side effects of levodopa treatment, it has been found that the effectiveness of levodopa gradually declines with time until it is no longer effective. Also, an increased incidence of malignant melanoma has been observed in patients undergoing treatment with levodopa. Accordingly, the use of levodopa in the treatment of Parkinson's disease is far from ideal.
An alternative approach to the treatment of Parkinson's disease is the use of drugs that mimic the action of dopamine. Such drugs are collectively known as dopamine agonists because they directly stimulate dopamine receptors within the dopamine-deficient nigrostriatal pathway. Unlike levodopa, dopamine agonists do not need to be converted in the brain to active compounds. Also, dopamine agonists are effective in patients in the advanced stages of Parkinson's disease when levodopa is no longer effective because they act directly on the dopamine receptors and are therefore unaffected by the lack of dopamine-producing nerve cells in such patients. However, the action of such dopamine agonists on the dopamine receptors also causes unwanted dopaminergic effects, such as nausea, vomiting and extrapyramidal effects, which can be debilitating and some dopamine agonists, such as apomorphine, are associated with further undesirable side effects, especially when high doses are used, such as sedation, respiratory depression, hypotension, bradycardia, sweating and yawning.
The severity and nature of such side effects can be affected by the mode of administration of the drug. For instance, studies involving apomorphine have investigated a variety of routes for administration of this drug. However, oral administration of apomorphine tablets has required high doses to achieve the necessary therapeutic effect because apomorphine administered by this route undergoes extensive presystemic metabolism in the small intestine and/or liver (the first pass effect). Also, long-term studies involving such oral forms were stopped after 7-10 days due to unexplained rises in blood urea nitrogen. Sub-lingual administration of apomorphine tablets caused severe stomatitis on prolonged use with buccal mucosal ulceration in half the patients treated. Intranasal administration produced transient nasal blockage, burning sensation and swollen nose and lips and, in some of the patients tested, had to be withdrawn because of what was considered to be chemical inflammation of the nasal mucosa. Accordingly, the only satisfactory way of administering apomorphine which avoids high first pass metabolism has been found to be subcutaneous administration and, thus, the only commercially available formulation of apomorphine is a liquid for subcutaneous injection or subcutaneous infusion. Even so, subcutaneous administration does not avoid the normal dopamine agonist side effects, such as nausea and vomiting, and subcutaneous administration, whether by injection or infusion, is not easy to accomplish, particularly by patients whose motor functions are already impaired, and therefore requires training of patients and caregivers. Also, the injection site must be changed every 12 hours to minimize risks of skin discoloration and nodules forming. In view of these problems, it is not surprising that the use of dopamine agonists, such as apomorphine, in the treatment of Parkinson's disease has been largely confined to the treatment of "off" periods caused by levodopa therapy despite the obvious clinical benefits of such drugs over levodopa.
It is apparent from the above that it would be highly desirable from a clinical point of view to find a way of administering dopamine agonists, such as apomorphine, which is easy for the patient to accomplish thereby reducing the need for supervision, and which bypasses first pass metabolism in the liver. According to the present invention there is provided a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, a dopamine agonist, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
It has been found that such fast-dispersing dosage forms promote pre-gastric absorption of the active ingredient, that is, absorption of the active ingredient from that part of the alimentary canal prior to the stomach. The term "pre-gastric absorption" thus includes buccal, sublingual, oropharyngeal and oesophageal absorption. Dopamine agonists absorbed by such pre-gastric absorption pass straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of dopamine agonists absorbed in this way may also be increased. This means that the dose of such dopamine agonists may be reduced while still producing the desired beneficial effects and this decrease in dose will result in a corresponding reduction of unwanted side effects.
In addition, clinical studies have shown that 23-52% of patients with Parkinson's disease have swallowing difficulties and many such patients tend to dribble. Accordingly, such fast-dispersing dosage forms have the further advantage that they will disintegrate rapidly in the mouth thereby minimizing the above problems as large volumes of water will not be co-administered. It is therefore anticipated that such fast-dispersing dosage forms will be easier for patients to take and easier for caregivers to administer.
One example of a fast-dispersing dosage form is described in U.S. Pat. No. 4,855,326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a "candy-floss" preparation. The spun "candy-floss" product is then compressed into a rapidly dispersing, highly porous solid dosage form.
U.S. Pat. No. 5,120,549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix-forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
U.S. Pat. No. 5,079,018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0.degree. C. or below to leave spaces in place of hydration liquid.
Published International Application No. WO93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and then removing water by forced air or vacuum drying.
U.S. Pat. No. 5,298,261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.
U.S. Pat. No. 5,073,374 to McCarthy discloses a compressed tablet dosage form composed of 90-99% by weight of a water-soluble excipient (sucrose, lactose or sorbitol) and a bucally absorbable active agent. McCarthy also requires 1-3% by weight of a pharmaceutically acceptable lubricant such as a magnesium stearate or sodium dodecyl stearate which is added so that disintegration occurs from about 0.5 to 5 minutes after administration. In contrast, the dosage form according to the present invention does not include a lubricant. In fact, the presence of a lubricant would detrimentally impact upon the disintegration times of the present invention. Further, there is no mention or suggestion in McCarthy of sublimation, a required element in the presently claimed pharmaceutical dosage form.
U.S. Pat. No. 5,529,789 to Lo discloses a process dependent composition to achieve rapid dissolution utilizing a water-soluble, menthol-soluble component. After subliming menthol from the pharmaceutical composition, a solid, water-soluble polymer matrix remains. Lo teaches the use of a menthol-soluble polymer rather than a sugar as the soluble excipient.